Anthelmintic 2-imidazolin-2-ylbenzimidazoles



United States Patent 3,482,022 ANTHELMINTIC Z-IMIDAZOLIN-Z-YL-BENZIMIDAZQLES George Holan, Brighton, Victoria, and Eva Lea Samuel,

East Bentleigh, Victoria, Australia, assignors to Monsanto Chemicals(Australia) Limited, Westscray, Victoria, Australia, a company ofVictoria, Australia No Drawing. Original application Apr. 15, 1965, Ser.No. 448,271, now Patent No. 3,365,462, dated Jan. 23, 1968. Divided andthis application Sept. 28, 1967, Ser.

Int. Cl. A01n 9/22 US. Cl. 424-273 2 Claims ABSTRACT OF THE DISCLOSURE Amethod of treating helminthiasis by administering to animals atherapeutic amount of a compound of the formula:

wherein R and R are each selected from the class consisting of hydrogen,chlorine, bromine, alkyl of not more than carbon atoms, and alkoxy ofnot more than 5 carbon atoms; and wherein R and R are each selected fromthe class consisting of hydrogen and alkyl of not more than 5 carbonatoms; or a composition containing said compound.

This application is a division of copending application Ser. No.448,271, filed Apr. 15, 1965, now US. Patent 3,365,462. r

This invention provides new 2-substituted benzimidazoles, in particular,2-imidazolin-2-yl-benzirnidazoles, which have been shown to be useful asbiological toxicants especially as anthelmintics.

The new compounds of the invention are the2-imidazolin-Z-yl-benzimidazoles having the structural formula:

and the salts and N-acyl derivatives of such compounds, wherein R and Rdenote hydrogen or substituent groups selected from halogen, alkylradicals containing not more than five carbon atoms, or alkoxy radicalsin which the alkyl portion contains not more than five carbon atoms; andwherein R and R denote hydrogen or alkyl radicals containing not morethan five carbon atoms. The halogen preferably is chlorine or bromine,while the alkyl radical preferably is methyl, and the alkoxy preferablyis methoxy. The N-acyl derivatives preferably are the N-acetyl orN-benzoyl derivative, which convert, by hydrolysis to the parent base ofthe above formula. The salts are preferably the acid-addition salts,such as the hydrochloride, sulphate, and nitrate, provided by mineralacids; or such as the acetate, glycolate, and stearate, provided byaliphatic carboxylic acids; or such as the phthalate, p-aminobenzoate,and salicylate, provided by aromatic carboxylic acids. Certain of thesesalts, such as the hydrochloride and acetate, are more soluble in waterthan the parent base, hence they are more suitable for someapplications. When applied as anthelmintics it is, of course, essentialthat the acid moiety of the present compounds be non- 3,482,022 PatentedDec. 2, 1969 "ice wherein R R R and R are as denoted above, byconventional procedure for benzazole synthesis.

Thus, the compounds of the invention may be prepared by reactingtogether an imidazolin-Z-yl-Z-carboxylic acid and an o-phenylene diaminein the presence of polyphosphoric acid at about 250 C. In order to avoidundue loss of the imidazoline carboxylic acid component bydecarboxylation, it is often preferable to start with a lower alkylester of the carboxylic acid, however, the amide of the carboxylic acidmay be employed in place of the ester. Alternatively, when the aldehydeis employed as starting material for the condensation with ano-phenylene diamine, it is necessary to use an oxidising medium for thereaction, good results being obtained using nitrobenzene as solvent. Asan example, an o-phenylene diamine and 2-imidazo1ine-2-aldehyde areheated in nitrobenzene solution for a short time at the refluxtemperature. In a modification of this procedure, the aldehyde anddiamine are first condensed together to form a Schiffs base which isthen cyclised to the benzimidazoic by treatment with an oxidising agent,such as cupric acetate or air, in the presence of a dehydrogenationcatalyst.

Since Z-imidazoline carboxylic acids and aldehydes are comparativelydiflicult to prepare, a preferred course is to start with abenzimidazole which is substituted in the 2-position with a suitablereactive group and condense this with ethylene diamine to give thedesired compound, as illustrated in the following equation:

N a a R H y R rr-g-m 3 wherein R R R R are as denoted above and Yrepresents a group selected from --COOH; COOR; -CONH CN;

NH.HC1 o and CCl wherein R signifies alkyl radicals containing not morethan five carbon atoms.

'We prefer, however, to start with the Z-trichloromethyl benzimidazoles,which react simply with thylene diamine (or substituted ethylenediamines) to give the required imidazolinyl derivatives in very highyield, as illustrated in the following equation:

wherein R R R and R are as denoted above. Thus, 2-trichloromethylbenzimidazole reacts spontaneously on mixing with an excess of ethylenediamine at room temperature to give 2-(2-imidazolin-2-yl) benzimidazolein quantitative yield. An inert diluent or solvent, such as1,2-dimethoxyethane or ethyl acetate can be used to give a more easilycontrolled reaction. The order of mixing of reagents is not critical,which applies also to the molar proportion, however, an excess of thediamine is preferred since this then serves to neutralise the hydrogenchloride formed in the reaction. The product is separated from solventand the diamine hydrochloride by conventional methods.

Illustrative member compounds embraced by the structural formula above,defining the compounds of the invention, are2-(2-imidazolin-2-yl)-benzimidazole; 2-(2'-imidazolin 2-y1)-5,6-dimethylbenzimidazole;2-(2-imidazolin-2-yl)-5,6-dichlorobenzimidazole; 2-(2'-imidazolin 2'-yl)-5-chlorobenzimidazole; 2-(4'-methyl-2-imidazolin-2'-yl)-3-methylbenzimidazole; 2-(2-imidazolin 2-yl) 5- nitrobenzimidazole;and 2-(2-imidazolin-2-yl)-5-methy1- benzimidazole.

Preparation of the new compounds of the invention is illustrated in thefollowing non-limitative practical examples.

EXAMPLE 1 Ethylene diamine (9 ml., 0.15 mole) was added gradually withcooling to a solution of 2-trichloromethylbenzimidazole (4.8 g., 0.02mole) in 1,2-dimethoxyethane. After minutes, the solution was dilutedwith water giving 2-(2'-imid'azolin-2'-y1)-benzimidazole as a pale buffsolid (93% yield). Recrystallisation from aqueous acetone gavecolourless needles, M.P. 280 C.

Analysis of the product C H N resulted. Found: C, 64.7; H, 5.6; N, 29.7.Requires: C, 64.5; H, 5.4; N, 30.1% The N-acetyl derivative of thespecified compound had a melting point of 211 C.

EXAMPLE 2 1,2-propanediamine (4.2 g., 0.05 mole) was added gradually toa hot solution of 2-trichloromethylbenzimidazole (4.8 g., 0.02 mole) in1,2-dimethoxyethane (50 ml.). An exothermic reaction developed and thereaction mixture boiled. The mixture was allowed to cool to roomtemperature over one hour, then solids were filtered off. The solidconsisted of propylene diamine hydrochloride together with some of therequired product (0.8 g.), which was separated from the hydrochloride bywashing with water. Dilution of the reaction mother liquor withpetroleum ether gave 'a further amount (1.2 g.) of the required product.The combined product was recrystallised from chloroform'and from ethylacetate giving 2-(4'- methyl 2-imidazolin-'2'-yl)-benzimidazole ascolourless crystals, M.P. 252 C.

EXAMPLE 3 Ethylene diamine (0.6 g., 0.01 mole) was added gradually to ahot solution of 5 6)-chloro-2-trichloromethylbenzimidazole (1.4 g.,0.005 mole) in alcohol. The mixture was allowed to stand for a few hoursafter the addition was completed. The precipitated ethylene diaminehydrochloride was filtered off, the alcoholic solution was diluted withwater to give some unclean product. Addition of 10% sodium carbonatesolution precipitated 2-(2'-imidazolin-2'-yl)-5(6)-chlorobenzimidazoleas whit crystals (50% yield). Recrystallisation from acetonitrilc gavecolourless needles, M.PL 245 C.

Analysis of the product C H N Cl resulted. Found: C, 54.0; H, 4.1; N,25.3. Requires: C, 54.4; H, 4.1; N, 25.4%.

EXAMPLE 4 Ethylene diamine (4.5 g.) was added slowly to a cooledsolution of 5-methyl-2-trichloromethylbenzimidazole (7.5 g.) inchloroform (150 ml.). Next day the precipitate of ethylene diaminehydrochloride was removed and petroleum ether was then added toprecipitate 2-(2'-imidazolin-2'-yl)-5-methylbenzimidazole in yield.After recrystallisation from benzene the solid had M.P. 240 C.

Found C H N C, 66.3; H, 6.1; N, 28.1. Requires: C, 66.0; H, 6.0; N,28.0%.

' EXAMPLE 5 5-nitro-2-trichloromethylbenzimidazole (14 g.) was added toa solution of ethylene diamine (20 g.) in water (250 ml.). Next day, thesolid precipitate was filtered off and recrystallised from butanol. The2-(2'-imidazolin-2'- yl)-5-nitrobenzimidazole (80% yield) had M. P. 325C.

Found C H N O C, 51.7; H, 4.2; N, 29.8. Requires: C, 51.9; H, 3.9; N,30.3%.

The new compounds of the invention are useful in combattinghelminthiasis, i.e. in treating animals susceptible to or suffering froman infestation of the gastrointestinal tract with parasitic worms, byadministering to the animals a prophylactic or a therapeutic amount ofat least one such compound. Said compounds combine a high degree ofactivity towards the parasites with a low toxicity toward the host, and,moreover, are relatively economical to manufacture. The anthelminticactivity of said compounds was assessed by the modified McMaster eggcounting technique as described by H. B. Whitlock and H. McL. Gordon; J.Council Scientific Industrial Research (Australia) 12; p. 50, 1939 andH. B. Whitlock, J. Council Scientific Industrial Research (Australia)21; p. 177, 1948. Thus, lambs 4-5 months old were infested with larvaeof Haemonchus contortus. The faeces of the lambs infected were examinedat intervals for eggs of Humanchus contortus to ensure that theinfestation had been effective. The lambs were then dosed with the testcompounds at rates of mg./kg. of body weight and 50 mg./kg. of bodyweight, two lambs being included in each treatment group. Anthelminticefiiciency was assessed by determining the number of eggs per gram infaeces passed on each of the seven days following treatment. A 100%reduction in egg count was found at both rates specified, indicating ahigh anthelmintic efiiciency.

Veterinary anthelmintic formulations embodying the new compounds of theinvention for treatment of helminthiasis can be either as a liquidsuspension ready to use or, as a wettable or water-dispersible powderwhich is mixed with water prior to use. A liquid-suspension formulationmay contain from 50-55% w./v. of the active compound together with adispersing agent and stabilizing agent. A typical formulation is asfollows:

Active compound 50-55 parts weight.

Dispersing agent /2-2 parts weight.

Stabilising agent 1-3 parts weight.

Preservative As required Water Suflicient to make 100 volumes.

Suitable dispersing agents are those containing sulphonate groups, forexample, sodium lignin sulphonate or the sulphonated phenol or naphtholformaldehyde polymers. Bentonine may be employed as the stabilisingagent, although it is possible to use such protective colloids ascarboxy methyl cellulose, sodium alginate and the like. The formulationscan be prepared by mixing the active compound/s and water containingdissolved dispersing agents very vigorously by means of suitablemechanical mixing equipment. A wettable or water-dispersable powderformulation may contain about 90-95% w./w. of the active compoundtogether with a Wetting agent and dispersing agent. A diluent such akaolin can also be added if a concentration below about 98% w./w. isrequired. An anti-foaming agent, and, in some cases, a stabilising agentmay be present. A typical formulation is as follows:

Active compound 90-95 parts weight. Wetting agent /24 parts weight.Stabilising agent 0-2 parts weight. Anti-foaming agent 0.01-1 partsweight. Water 0-5 parts weight.

Suitable wetting agents are the non-ionic alkylphenolethylene oxideadducts, such as an octylphenol or nonylphenol condensed with ten molesof ethylene oxide, or anionic materials such as the synthetic arly alkylsulphonates, examples of which are sodium dodecyl benzene sulphonates,or sodium dibutyl napthalene sulphonate. In general about 1% w./w.wetting agent is required. The anti-foaming agent employed may be eithera silicone or such materials as ethyl hexanol, octanol and the like; andthe stabilising agent may again be chosen from bentonite or thewater-soluable gums. Wettable or waterdispersible powder formulationsare prepared by careful and adequate mixing of the active compound withother ingredients with or without the addition of some water usingtypical powder blending equipment such as ribbon blender. The powder isstirred into water by the user before application in the field.

The salts and N-acyl derivatives of the 2-imidazolin-2-yl-benzimidazoles of the invention may be prepared from the indicatedbases themselves by conventional procedure, as will be understood bypersons skilled in the art. Al-

wherein R and R are each selected from the class consisting of hydrogen,chlorine, bromine, alkyl of not more than 5 carbon atoms, alkoxy of notmore than 5 carbon atoms, and wherein R and R are each selected from theclass consisting of hydrogen and alkyl of not more than 5 carbon atoms.

2. A method of combatting helminthiasis in an animal which comprisesadministering to an animal suffering therefrom, an anthelmanticallyeffective amount of a 2- imidazolin of the structure:

H H I /NC-R4 Rz- C C I N/ N o R wherein R and R are each selected fromthe class consisting of hydrogen, chlorine, bromine, alkyl of not morethan 5 carbon atoms, alkoxy of not more than 5 carbon atoms, and whereinR and R are each selected from the class consisting of hydrogen andalkyl of not more than 5 carbon atoms.

References Cited UNITED STATES PATENTS 3,166,563 1/1965 Epstein et a1260-304 3,050,526 8/1962 Chien-Pen Lo 260-304 3,000,784 9/1961 Todd167-53 3,006,810 10/1961 Shinn et al. 16753 3,102,074 8/1963 Brown 167533,137,578 6/1964 Selms 260-3092 ALBERT T. MEYERS, Primary Examiner I. V.COSTIGAN, Assistant Examiner

